Naturwissenschaften (2004) 91:355–365
DOI 10.1007/s00114-004-0541-9
REVIEW
Jerome Siegel
Brain mechanisms that control sleep and waking
Published online: 2 July 2004
Springer-Verlag 2004
Abstract This review paper presents a brief historical
survey of the technological and early research that laid
the groundwork for recent advances in sleep–waking research. A major advance in this field occurred shortly
after the end of World War II with the discovery of
the ascending reticular activating system (ARAS) as the
neural source in the brain stem of the waking state.
Subsequent research showed that the brain stem activating system produced cortical arousal via two pathways: a
dorsal route through the thalamus and a ventral route
through the hypothalamus and basal forebrain. The nuclei,
pathways, and neurotransmitters that comprise the multiple components of these arousal systems are described.
Sleep is now recognized as being composed of two very
different states: rapid eye movements (REMs) sleep and
non-REM sleep. The major findings on the neural mechanisms that control these two sleep states are presented.
This review ends with a discussion of two current views
on the function of sleep: to maintain the integrity of the
immune system and to enhance memory consolidation.
Historical background
Three advances in technology and a clinical research
finding during the first half of the twentieth century were
critical for laying a foundation for the scientific advances
that were generated in the latter half of the twentieth
century.
This article is based in part on material in the book “The neural
control of sleep and waking” (J. Siegel, 2002).
J. Siegel ())
University of Delaware,
Newark, DE 19716, USA
e-mail: jsiegel@udel.edu
J. Siegel
Warsaw School of Social Psychology,
Chodakowska 19/31, 03-815 Warsaw, Poland
Electroencephalography
The single most important tool for the scientific study of
sleep and waking has been the electroencephalograph.
This instrument records electrical activity of the brain and
provides an objective measure of the state of the brain and
the states of consciousness. Hans Berger in Jena, Germany, is credited with developing the first instrument that
recorded electrical activity generated by the human brain.
Berger, in 1925, had access to one of the first vacuum
tube amplifiers manufactured by the Siemens Company
and used this sensitive galvanometer to record the electrical activity from his young son’s brain. This landmark
electroencephalographic (EEG) recording was published
by Berger in 1929 (Berger 1929). This important advance
was built upon earlier research with animals that demonstrated the electrical nature of neural activity (Brazier
1961).
Berger’s early work showed a clear EEG difference
between sleep and waking. Research conducted 24 years
later (Aserinsky and Kleitman 1953), showed that the
EEG during sleep could be differentiated into at least two
categories. One type of sleep was found to be associated
with the occurrence of dreams and the other with nondream sleep. Since dream sleep was found to be accompanied by episodes of rapid eye movement (REM), this
state is often called REM sleep. Non-dream sleep is also
called non-REM sleep. Figure 1a shows examples of EEG
tracings during waking and during different stages of
sleep.
An awake record is characterized by EEG waves that
are low voltage (5–50 V) and high frequency (20–40 Hz)
relative to voltages and frequencies seen during non-REM
sleep. When a person falls asleep, a brief transitional state
between waking and sleep is characterized by an EEG
that resembles waking. During this period, recordings
from electrodes placed on the skin around the eyes show
the presence of sporadic slow eye movements. This transitional state is referred to as stage 1 sleep. As the individual progresses toward deeper sleep, stages 2, 3, and 4,
the EEG shows higher amplitudes and lower frequencies.
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waking, there are higher amplitude and slower frequency
components in the 4–7 Hz range. This sleep state is often
called low-voltage, REM, or dream sleep. Since the person is clearly asleep, but paradoxically the EEG looks like
that of an awake person, this state is also referred to as
paradoxical sleep.
Slow-wave sleep followed by a REM sleep episode is a
pattern that repeats throughout the night. Each cycle of
non-REM sleep followed by a REM episode is about
90 min in duration and typically yields five sleep cycles
in an 8 h sleep period. Figure 1b is a hypnogram that
graphically summarizes the sleep stages during a typical
night’s sleep.
The stereotaxic instrument
Fig. 1 a Examples of typical EEG recordings during waking and
the different stages of sleep [reproduced from Purves et al. (1997)
with the permission of Sinauer Associates, Sunderland, Mass.]. b A
typical hypnogram which illustrates the progression of sleep stages
as they cycle through an 8-h period of sleep. This graph shows that
the deeper stages of non-REM sleep occur during the first half of
the night and the durations of REM sleep increase during the course
of the night [reproduced with permission from Siegel (2002) with
the permission of Springer-Verlag, New York]
Electrical recordings that are most accessible from the
brain and that are most revealing of the states of sleep and
waking are from the cortical surface of the brain. However, the state of the cerebral cortex is not controlled by
the cortex itself; it is controlled by structures below the
cortical surface that cannot be approached under direct
visual control. The stereotaxic instrument permits probes
to be accurately inserted into the brain to experimentally
manipulate deep structures and thus determine their influence on sleep and waking. Such manipulations include
lesions to destroy neural tissue, electrical stimulation, and
the application of chemicals. The first such device to be
widely used was developed in London, England in the
early 1900s by two neurosurgeons, Victor Horsley and
Robert Clarke (Clarke and Horsley 1906; Marshall and
Magoun 1990, 1991).
The stereotaxic instrument fixes the head in a standard
orientation with respect to a probe drive and attached
probe that can be moved above the skull and brain in the
anterior–posterior (front-to-back) and medial–lateral (left
and right) dimensions. The probe can then be lowered in
the vertical dimension through a hole in the skull into the
brain. Clarke and a collaborator developed an atlas of the
human brain with plates that corresponded to the sagittal
plane of the Horsley–Clarke stereotaxic instrument. The
instrument in conjunction with the atlas permitted a probe
to be positioned with considerable accuracy to a target
deep within the brain. The subsequent development of
stereotaxic instruments and brain atlases of different animal species was a great resource for brain research in
general and for sleep–waking research in particular.
The cathode ray oscilloscope
The deepest stage of non-dream sleep (stage 4 sleep)
exhibits the highest amplitudes (100–400 V) and lowest
frequencies (0.5–3 Hz). Stages 3 and 4 are often referred
to as slow-wave or high-voltage sleep. When the person
enters a dream state, during which REMs occur, the EEG
rapidly shifts from the slow-wave pattern to a pattern
that resembles a waking and stage 1 sleep record. In addition to the low-voltage, high-frequency EEG seen during
The third technological advance that furthered understanding of the neural control of sleep and waking was the
cathode ray tube. This device was necessary to explore
the electrical activity of the brain at the single cell level.
The voltage change of a single active brain cell (the action
potential) occurs on the order of 1–3 ms. An electromechanical galvanometer, like an EEG-type recorder, does
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not have a response time capable of tracking such a rapid
voltage change. The electron beam of a cathode ray tube
has virtually no inertia and can respond with millisecond
and submillisecond speeds. When a microelectrode probe
is placed within or near a nerve cell, the neural signal
from that single neuron can be amplified and fed into a
cathode ray oscilloscope and deflect its beam as the cell
fires its action potential.
Two early pioneers of this technology were Joseph
Erlanger and Herbert Gasser in St. Louis, Missouri in
1922. They recorded the compound action potential of
whole nerves that contained the axonal processes of
many nerve cells (Gasser and Erlanger 1922; Erlanger
and Gasser 1924). The technique was soon applied, using
fine-tipped microelectrodes, to the recording of single
nerve cell action potentials. This approach permitted the
discovery of neural events at the cellular level that occur
during sleep and waking.
Encephalitis lethargica
A number of findings prior to the modern era of sleep–
waking research were important, but the one advance that
provided the first knowledge of brain regions central to
sleep and waking occurred during the final years of World
War I. During the period 1917–1919, a worldwide influenza epidemic produced an enormous number of fatalities. An estimated 25–40 million people died from what
was commonly called the Spanish Flu.
Constantin von Economo, a psychiatrist and neurologist at the University of Vienna, saw a number of patients
who had contracted the virus and exhibited symptoms of a
variant of the disease that caused a sleep coma. This form
of the disease was called encephalitis lethargica and was
usually fatal. Von Economo, also a skilled neurohistologist, analyzed the brains of these patients and discovered
the area that was severely damaged and caused the fatal
sleep coma. His histology, utilizing a stain selective for
cell bodies, revealed a profound loss of cells in the posterior hypothalamus and adjacent region of the mesencephalic reticular formation. This was the first evidence
that these structures were necessary to maintain the waking state. Recent evidence suggests that the selective brain
cell damage was caused not by an influenza virus but was
due to an autoimmune disorder (Dale et al. 2004).
Another population of patients showed the opposite
symptoms, namely an inability to sleep. Brain histology
revealed a loss of cells in the anterior hypothalamus and
the adjacent preoptic area of the basal forebrain. This was
evidence for a brain region that is critical for the ability to
sleep.
These findings, published in a series of papers beginning in 1923 (von Economo 1923, 1930) provided the
first evidence of brain structures that are important for
waking, the posterior hypothalamus and anterior reticular
formation, and structures important for sleep, the anterior
hypothalamus and preoptic area. Figure 2 is a schematic
drawing of the cat brain that shows the locations of these
Fig. 2 Drawing of a cat brain based on a sagittal section close to
the midline. This view shows the location of the reticular formation
and other brain structures. Also represented are the boundaries
(dashed lines) that demarcate the five subdivisions of the brain: the
medulla oblongata and pons (hindbrain), the mesencephalon (midbrain), and the diencephalon and telencephalon (forebrain). Abbreviations: AC anterior commissure, BFB basal forebrain, OB olfactory bulb, OC optic chiasm, POA preoptic area [reproduced with
permission from Siegel (2002) with the permission of SpringerVerlag, New York]
regions of the brain. Figure 2 also shows the demarcations
between the major subdivisions of the brain: the medulla oblongata, pons, and mesencephalon, which comprise
the brain stem; and the diencephalon and telencephalon,
which comprise the forebrain.
The neural structures and pathways for arousal
Shortly after the end of World War II, Giuseppi Moruzzi
of the University of Pisa in Italy and Horace Magoun
of Northwestern University in Illinois collaborated on a
study conducted in Magoun’s laboratory. They electrically stimulated the mesencephalic reticular formation of
cats when the EEG recorded from the cerebral cortex
signified a sleep-like state. Upon the onset of stimulation there was a rapid and dramatic change of the EEG
to that of an awake brain (Moruzzi and Magoun 1949).
Figure 3 from their landmark paper shows the EEG activation produced by the reticular formation stimulation.
Subsequent work showed that destruction of the area stimulated by Moruzzi and Magoun produced animals with
constant sleep-like behavior and EEG records (Lindsley
et al. 1949, 1950; French et al. 1952). These findings
were experimental confirmations of von Economo’s clinical observations that damage to the reticular formation in
encephalitis lethargica patients abolished the waking
state. Based on these findings, the reticular formation in
the rostral region of the brain stem and the neural pathways basic to the cortical arousal response became known
as the ascending reticular activating system (ARAS). This
concept has remained central in the sleep–waking field.
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Fig. 3 Activation of the cerebral cortex by electrical stimulation of
the reticular formation in the cat. This figure, from Moruzzi and
Magoun’s original paper of 1949, shows four channels of EEG
cortical recordings during a period of high-voltage slow waves,
characteristic of sleep. The horizontal line below the bottom EEG
tracing marks the duration of stimulation to the reticular formation.
It is readily seen that the reticular stimulation abruptly changed the
cortical EEG from that of a sleep record to that of waking. At the
offset of stimulation, with the reticular activating influence removed, the EEG returned to the slow waves of sleep [adapted from
Moruzzi and Magoun (1949) with the permission of Elsevier Science, Amsterdam]
Fig. 5 The nuclei and pathways of the dorsal and ventral components of the ascending activating system that originate in cholinergic cells of the reticular formation. The dorsal pathway, represented by solid lines, activates the cortex via the thalamus. The
ventral pathway (dashed lines) shows the involvement of the hypothalamus and basal forebrain in cortical activation. Abbreviations: OB olfactory bulb, OC optic chiasm, RF reticular formation
[adapted from Jones (2000) with the permission of WB Saunders,
Philadelphia]
Fig. 4 A drawing of a frontal section through the brain stem of a
cat showing the location of the peribrachial nuclei. The solid circles
on the right represent cells of the ascending arousal system that
synthesize and release acetylcholine. Abbreviations: bc brachium
conjunctivum, CNF cuneiform nucleus, DR dorsal raphe nucleus,
IC inferior colliculus, LDT laterodorsal tegmental nucleus, ll lateral
lemniscus, PPT pedunculopontine tegmental nucleus [adapted from
Jones and Beaudet (1987) with the permission of Wiley-Liss, New
York]
Subsequent to the pioneering work of Moruzzi and
Magoun, research has revealed the specific nuclei and
cell types of the reticular formation that produce cortical
arousal. Coursing through the pontine and mesencephalic
brain stem is a prominent fiber tract, the brachium conjunctivum, which carries signals from the cerebellum to
the thalamus. Surrounding this fiber tract at the level of
the pontine–mesencephalic junction are two nuclei, the
pedunculopontine tegmental nucleus (PPT) and the laterodorsal tegmental nucleus (LDT). The two nuclei are
called the peribrachial nuclei. Using immunohistochemical techniques, Jones and Beaudet (1987) have shown that
these nuclei contain acetylcholine-synthesizing neurons.
These are the major cells of the ascending arousal system.
Figure 4 shows the location of the peribrachial nuclei of
the cat brain and the cholinergic cells located there.
Using a variety of neuroanatomical tracing techniques,
cortical arousal from activation of the peribrachial nuclei
is now known to be mediated by two routes: a dorsal and a
ventral pathway. Figure 5 is a schematic representation of
the nuclei and fiber tracts of these two pathways. The
dorsal pathway is fairly direct. Peribrachial cells project to
a group of nuclei named for their location in the thalamus: the midline and intralaminar nuclei of the thalamus.
These nuclei project to broad areas of the cortex (Nauta
and Kuypers 1958; Saper and Loewy 1980; Macchi and
Bentivoglio 1986) and are often referred to as the nonspecific or diffuse projection nuclei of the thalamus. When
activated, the terminals of these fibers release glutamate,
an excitatory amino acid neurotransmitter, and produce an
arousal of the entire cerebral cortex.
The ventral pathway takes a more complex route to the
cortex. Prior to reaching the thalamus, components of the
tract from the reticular formation diverge from the dorsal
bundle and course into and through the ventral region of
the forebrain. The ventral pathway has been described by
Jones (1993, 2000). In the ventral diencephalon, these
fibers synapse upon cells of the tuberomammillary nucleus of the posterior hypothalamus. Cells of this hypothalamic nucleus project to the entire cerebral cortex and
release histamine at their terminals. Histamine, a novel
transmitter in the brain found only in these cells, has a
strong arousal effect upon the cerebral cortex (Lin et al.
1988; Saper 1985, 1987).
Another population of cells recently discovered in the
hypothalamus utilizes a peptide neurotransmitter called
orexin or hypocretin. These cells also project to the cerebral cortex and produce arousal (Kilduff and Peyron
2000; Moore et al. 2001; Peyron et al. 1998). The popu-
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lations of hypocretin and histamine neurons are both located in the posterior hypothalamus (Hopkins et al. 2001)
and appear to innervate each other and cooperate to regulate arousal (Eriksson et al. 2001).
The ventral pathway from the cholinergic reticular
formation continues more rostrally into the basal forebrain to terminate in cells that also synthesize acetylcholine. These basal forebrain cholinergic neurons project
to a number of regions including the cerebral cortex and
contribute to cortical arousal. The two components of the
ventral pathway, the hypothalamus and basal forebrain,
are shown in Fig. 5.
It appears that cortical arousal has its main control in
cholinergic cells of the reticular formation. This brain
stem influence is mediated by the dorsal (thalamic) and
ventral (hypothalamic and basal forebrain) pathways that
utilize their own neurotransmitters to activate the cortex, namely, glutamate, histamine, hypocretin, and acetylcholine. In addition, other brain stem nuclei provide
serotonergic, noradrenergic, and dopaminergic influences
to the cortex that modulate the sleep and waking states
(Saper 1987).
The fact that there are multiple pathways and neurotransmitters that control cortical arousal helps us understand a clinical phenomenon. After various types of brain
damage that cause a sleep-like coma, there is often some
degree of recovery of function. This may be due to the
multiple and somewhat redundant nature of the neural
pathways that contribute to arousal.
The neural control of non-REM sleep
Evidence has accumulated that non-REM or slow-wave
sleep is produced by inhibition of one or more of the
influences that produce arousal. Electrical stimulation to a
number of brain structures will produce the electrographic
signs of sleep and, in behaving animals, behavioral sleep.
In a series of experiments, Siegel and colleagues (Siegel
and Lineberry 1968; Lineberry and Siegel 1971; Siegel
and Wang 1974) showed that sleep-inducing stimulation
that produced EEG slow waves recorded from the cerebral cortex, produced at the same time an alteration of the
firing pattern of cells in the brain stem reticular activating
system. Cells of the reticular formation typically underwent a decreased firing rate and, in some cases, a complete cessation of neural activity. After the sleep-inducing
stimulation was terminated, there was a gradual recovery
of firing in brain stem neurons as the cortical EEG slow
waves shifted to a low-voltage waking record. This finding suggests that a sleep-inducing influence has its effect
by inhibiting the neural activity of the reticular activating
system.
The basal forebrain area, as described above, is involved in producing arousal. However, early experiments
had shown quite convincingly that stimulation of this
region in cats produced the EEG and behavioral signs of
sleep (Sterman and Clemente 1962a, 1962b). Later work,
as described by Jones (1993) and Saper et al. (1997),
showed that the basal forebrain cholinergic cells that project to the cortex mediate the basal forebrain-produced
arousal. In addition, the basal forebrain was shown to also
house neurons that synthesize and release gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter.
One target of these cells is the histaminergic neurons of
the posterior hypothalamus. It appears that the sleep-inducing effect of basal forebrain stimulation is not directly
on the cortex, but is mediated by the inhibitory effect of
GABA on the hypothalamic component of the arousal
system. Recall that von Economo reported insomnia (loss
of sleep) in patients who had suffered damage to the
preoptic basal forebrain area. This may now be seen
as due to the loss of the basal forebrain GABA inhibitory influence upon the posterior hypothalamus. Without
the basal forebrain inhibitory influence, the histaminergic arousal system remains active and prevents sleep.
Szymusiak and McGinty (1986) showed that insomnia in
basal forebrain-lesioned cats could be reversed with an
injection of muscimol, a drug that mimics the effects of
GABA, into the posterior hypothalamus. In addition to the
basal forebrain projection to the hypothalamus, there is
evidence that this population of inhibitory neurons also
projects to the peribrachial nuclei of the brain stem reticular activating system and contributes to the basal
forebrain induction of sleep.
There has always been an interest in exploring chemical factors that produce sleep. An easy-to-understand
impetus for this is the simple observation that as one
remains awake for a number of hours, a feeling of tiredness and an urge to sleep becomes stronger. It is as if a
chemical factor builds up and the longer one stays awake,
the more this chemical accumulates. When sleep occurs,
the chemical is removed or metabolized and the urge to
sleep is removed.
A classic approach to this area of interest has been
to deprive animals of sleep and extract chemical substances from the brain, blood, cerebral spinal fluid, or
urine and inject them into non-sleep-deprived animals.
Control animals, of course, receive similar infusions from
non-sleep-deprived donors. Positive findings were reported as early as 1909 by Ishimori in Japan and in 1913 by
Piron in France. Since then more advanced procedures
have also yielded findings and in some cases the active agent has been characterized (Monnier et al. 1963;
Pappenheimer et al. 1967; Schoenberger and Monnier
1977; Nagasaki et al. 1980).
Two major questions arise: the origin of the chemical
factor and the site of action in the brain that causes the
sleep. Krueger et al. (1985) discovered the complex chain
of events that produces increased sleep during an illness
produced by a bacterial infection. Invading bacteria stimulate phagocytic cells of the immune system to incorporate and digest the disease-causing bacteria. The skeletal
residues of bacteria include circulating muramyl peptides
that stimulate the immune system to synthesize a number
of protein molecules, cytokines, that in turn stimulate a
population of hypothalamic cells to produce the growth
hormone releasing hormone (GHRH). Endocrinologists
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have long known that GHRH produced by the hypothalamus travels by a blood-borne route to the anterior pituitary and causes the release of growth hormone from the
pituitary gland. Another group of cells in the hypothalamus also produces GHRH, but these cells project axons to
the nearby basal forebrain–preoptic area. The GHRH,
now as a neurotransmitter, activates the GABAergic basal
forebrain cells to inhibit the arousal systems of the posterior hypothalamus and brain stem reticular formation
and thus produce sleep.
Robert McCarley and colleagues at Harvard University
have explored an endogenous chemical that produces
sleep in non-pathological, normal conditions. Adenosine
is a purine product of the breakdown of adenosine triphosphate (ATP) during cellular metabolism. This occurs
in all cells, including nerve cells. Extracellular fluids from
two brain regions were sampled during sleep and waking in cats. Increased amounts of adenosine were present
in both samples taken during the waking state compared
with the sleep state (Porkka-Heiskanen et al. 1997). Since
neural activity, and thus brain cell metabolism, is greater
during waking than in sleep, the increased metabolite,
adenosine, is not surprising. The two brain regions investigated were the basal forebrain, known to regulate
sleep and arousal, and a nucleus of the thalamus that is
not involved in regulating these states. Both groups of
cells were more active in the waking state and both
generated increased amounts of adenosine during waking.
However, of interest and importance is the observation
that the basal forebrain neurons, in contrast to the thalamic cells, possess adenosine receptors. One class of
these receptors, A1 adenoreceptors, opens potassium channels and this results in an efflux of this positive ion to
produce a hyperpolarizaton of the cell. An increase of
internal negativity is a neural inhibitory condition. The
clear inference is that when the cholinergic cells of the
basal forebrain are more active to produce arousal, increasing amounts of adenosine are generated that eventually feed back to act on the adenosine A1 receptors of
these same cells to decrease their activity and thus reduce
arousal. McCarley’s group (Thakkar et al. 1999) directly
tested this position by applying different concentrations
of an A1 receptor agonist to the basal forebrain. They
demonstrated a dose-dependent decrease in the activity
of these cells. Thakkar et al. (2002) also reported that
the hypocretin arousal-producing cells of the posterior
hypothalamus also possess adenosine A1 receptors that
would serve to dampen arousal. Similarly, the cholinergic
cells of the brain stem reticular activating system possess
adenosine receptors that function in a negative feedback
process to self-regulate arousal. An emerging view is that
the final step in producing sleep is an inhibition of cells in
regions of the brain that produce arousal. The source of
inhibition may be other brain regions or may result from a
self-regulating process inherent in the arousal system cells
themselves.
The neural control of REM sleep
In 1953, a discovery by Eugene Aserinsky, a graduate
student at the University of Chicago, and Nathaniel
Kleitman, his mentor, triggered an immense interest in the
scientific study of dream sleep – as well as the study of
sleep in general. They reported that during episodes of
dream sleep, transient rapid eye movements (REMs) were
readily detected and could be documented on the same
paper record as the EEG waves. In addition, they found
that the EEG recorded during dream sleep closely resembled that of an awake, alert brain (Aserinsky and
Kleitman 1953). These two measures (REMs and an
awake-like EEG) were the first objective indicators of the
occurrence of dream sleep. Kleitman’s sleep laboratory
soon showed that all the subjects studied had REM sleep.
Even those who claimed they did not dream, when
awakened during a REM episode reported having a dream
experience. It should be pointed out that over the years
since the Aserinsky and Kleitman findings, there have
been reports of dream episodes when subjects were awakened from slow-wave sleep. Not all of these reports can
be dismissed as recollections of dreams that occurred
during a previous REM episode because some of these
reports occurred prior to the first REM period.
As these findings on REM sleep were being generated,
William Dement, another student in Kleitman’s laboratory, discovered the presence of REM sleep in cats
(Dement 1958). Very shortly after, Michel Jouvet in
Lyon, France, as well as other workers over the years,
reported that REM sleep episodes occurred in all mammalian species investigated and was seen also in other
vertebrates, but in limited amounts (Jouvet et al. 1959;
Jouvet and Valatx 1962; Ruckebusch 1962; Adey et al.
1963; Faure et al. 1963; Roldan et al. 1963; Hartmann
et al. 1967; Shurley et al. 1969; Cicala et al. 1970;
Schlehuber et al. 1974; Latash and Galina 1975; Allison
et al. 1977; Siegel et al. 1996, 1999). REM sleep was
shown to be a universal phenomenon in mammals and
dream sleep in humans could no longer be relegated
solely to the occult or to the psychoanalytic couch. REM
sleep, and sleep in general, was now taken seriously as a
legitimate subject for scientific investigation.
REM sleep has been differentiated from slow-wave
sleep in both humans and animals on the basis of a
number of physiological measures. The most obvious
were the rapid eye movements themselves and the awakelike EEG brain recordings. In addition there is an irregular
heart rate and increased blood pressure, respiratory rate,
and pupil diameter. These autonomic changes indicate a
heightened state of sympathetic activation. During REM
episodes, males show penile erection and females exhibit
comparable signs of sexual arousal. Non-autonomic components of REM sleep also are present. Muscle tonus in
striated-skeletal muscle is abolished. There is essentially a
paralysis of the whole body – with the exception of extraocular muscles that control eye movements and, most
importantly, muscles of the diaphragm that control respiration. Another component of REM sleep is the occur-
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rence of spike-like transient waves recorded from electrodes in the pons, lateral geniculate nucleus of the thalamus, and the occipital (visual) cortex. These intermittent discharges are called PGO waves. Finally, electrodes
placed into or close to the hippocampus show a very
regular six per second EEG rhythm called theta waves.
The biological or psychological significance of these
REM sleep components are in some cases clear, and in
other cases obscure. For example, the low-voltage, fastactivity EEG recorded from the cortex indicates a cognitively active brain, which is appropriate for the dream
state. The sympathetic activation suggests that dreams are
periods of emotional arousal and the paralyzed skeletal
musculature prevents the dream episode from being acted
out. In contrast, the “meaning” of hippocampal theta and
PGO spikes is not known.
From the mid 1950s, the neural control of REM sleep
and its component parts have been intensively studied.
Using the technique of surgical separation of the neuraxis
at different levels of the brain stem, investigators have
isolated the neural control of REM sleep to the pontine
brain stem (Batini et al. 1959a, 1959b; Jouvet 1962;
Siegel 1985). Additionally, finely placed lesions and focal
brain stimulation within the pons and adjacent regions
have revealed the cell groups responsible for a number of
the components of REM sleep.
One of the most salient features of REM sleep is the
awake-like EEG during the sleep state. As might be expected, the cholinergic peribrachial nuclei at the pontine–
mesencephalic junction, in conjunction with a neighboring region in the pons, is now recognized as the source of
the activated cortex during REM/dream sleep. Consistent
with the observation that dream sleep is emotionally
charged, brain-imaging studies indicate that the ventral
arousal pathway, which engages the hypothalamus and
other limbic system structures, subserves the cortical
arousal during REM sleep (Maquet et al. 1996; Braun et
al. 1997; Nofzinger et al. 1997).
Another prominent component of REM sleep is the
profound paralysis of skeletal muscles. REM sleep paralysis has been shown to be due to a small region of the
dorsal pons, the nucleus subcoeruleus. A lesion to this
nucleus abolishes the REM sleep paralysis. A very dramatic observation is that during REM sleep, cats with
such lesions became very active and agitated, as if they
were acting out an emotionally charged dream episode
(Sastre and Jouvet 1979; Hendricks et al. 1982).
The fact that there are multiple components to REM
sleep suggests that multiple brain regions are involved in
the control of this state. Studies suggest that the onset and
offset of REM sleep are controlled by nuclei and connecting circuits within the pons and medulla. Two papers published in Science in 1975 (Hobson et al. 1975;
McCarley and Hobson 1975) presented a model of reciprocal interaction between the neural activities of two
populations of cells that result in the onset and offset of
REM sleep episodes. With the empirical data collected at
the time, this was an elegant attempt to explain, in neural
terms, the cycling process between periods of slow-wave
sleep and REM sleep. Since the publication of these papers, McCarley, Hobson, and others have collected additional data and have refined the model (Siegel 1985;
Hobson 1988; Steriade and McCarley 1990; Hobson et al.
1998; Xi et al. 1999; Chase and Morales 2000).
A current view is that the onset/offset of REM sleep is
due to increased activity of cholinergic cells of the peribrachial nuclei of the mesopontine brain stem. Increased
firing of these cells produces the cortical and limbic system activation seen during REM sleep. The offset of REM
sleep and the descent into slow-wave sleep is due to increased activity of cells of the locus coeruleus and dorsal raphe nucleus, also in the pons, which release norepinephrine and serotonin, respectively. These aminergic
neurotransmitters have an inhibitory effect on the cholinergic peribrachial neurons. The REM sleep episode is
thereby terminated. Neural activities of the REM-on and
REM-off nuclei are controlled by pontine negative feedback circuits that result in firing rates of these nuclei that
are reciprocally related. REM-on and REM-off activities
are also mediated by interneurons that utilize glutamate
and GABA. Additional nuclei and neurotransmitters of the
lower brain stem are recruited into the process and participate in the cortical arousal and muscle atonia that occur
during REM sleep.
The function of sleep
An indication that a state of quiescence, if not sleep, is a
very basic and important process is that all creatures, from
single celled organisms to humans, exhibit activity cycles.
There are periods of high activity levels interspersed with
episodes of rest. In the common fruit fly, Drosophila melanogaster, episodes of rest may be considered as
sleep, based on the following observations (Hendricks et
al. 2000; Shaw et al. 2000). During periods of rest, a
stronger sensory stimulus is required to elicit an orienting
response. This is comparable to sleep, as we know it,
during which a stronger stimulus is necessary to elicit a
response. More to the point, if fruit flies are prevented
from entering their resting state for a period of time and
then permitted to do so, the insects will show an increased
amount of time in the quiet state. This is comparable to
the rebound of sleep time after a period of sleep deprivation has been imposed in mammals. This suggests that
a homeostatic process regulates and programs a given
amount of time for sleep in insects as well as in humans
and other mammals. Moreover, periods of rest in Drosophila occur mainly during the dark phase of the 24-h
day, which reveals a circadian rhythm comparable to the
sleep–waking pattern seen in diurnal vertebrate species.
These observations, however, do not reveal the utility
or function of sleep. The approach most widely used to
explore this has been to deprive human and animal subjects of sleep and assess the effects. Since sleep clearly
exists as two distinct states, workers have attempted to
selectively deprive subjects of slow-wave sleep and of
REM sleep. A complication is that REM sleep normally
362
only follows a period of slow-wave sleep, so deprivation
of slow-wave sleep will also interfere with REM sleep.
But selective REM-sleep deprivation is feasible – as is
total sleep deprivation.
Evidence from the sleep literature suggests that sleep
serves at least two functions. A series of studies by Allan
Rechtschaffen and colleagues at the University of Chicago
has shown the dire effects of sleep deprivation in rats.
Within 2–3 weeks of total sleep deprivation all the rats
died. Selective deprivation of REM sleep also proved lethal, with the difference that survival time was 1 or 2
weeks longer (Rechtschaffen et al. 1983, 1989; Bergmann
et al. 1989; Kushida et al. 1989).
A number of changes occurred during sleep deprivation, but two have been identified as most important.
Sleep-deprived rats increased food intake as much as 80–
100% over their normal amount. However, they also
showed a significant weight loss. The reason for the
contradictory effects was a severe hypothermia that led to
a great increase in metabolic rate in the effort to regulate
body temperature toward a normal level. However, the
proximal cause of death proved to be a bacterial infection
that invaded the blood stream and spread throughout the
body. A recent experiment detailed the underlying process. Everson and Toth (2000) found that the source of the
bacteria was the gastrointestinal tract. Bacteria that are
normally contained within the intestine proliferate during
sleep deprivation, permeate the intestinal wall, and enter
the internal environment. The mesenteric lymph nodes
adjacent to the intestine normally protect against bacterial
invasion from the intestine, but under sleep deprivation
the immune system is compromised and ceases to defend
against this invasion (Everson 1993). The bacteria proliferate, spread to other organs, and eventually enter the
circulatory system to produce a systemic infection that is
fatal. It should be noted that sleep deprivation, especially
for long periods, acts as a non-specific stressor. Some
workers question whether the sleep deprivation per se or
the accompanying stress caused the dire effects described
above.
These dramatic and extreme effects were produced in
experimental animals. Humans normally do not experience such extreme conditions of sleep deprivation. Recent
studies report that the immune system is compromised
also by moderate sleep deprivation. After receiving vaccinations against influenza and hepatitis, subjects who
experienced moderate sleep deprivation showed a reduced
development of the antibodies that protect against these
diseases (Spiegel et al. 2002; Lange et al. 2003).
There is a growing body of literature that suggests
another function of sleep is the facilitation of memory
consolidation. There is evidence that the process of memory storage of a learning experience is enhanced during a
period of sleep that follows the learning. Experiments
with humans and animals show that subjects who are
trained on particular tasks and then permitted to sleep
retain the learned information better than subjects who are
prevented from sleeping after the learning.
Recognizing the possible confounding of the effects of
sleep deprivation with the effects of stress, experiments
have been designed to study the role of sleep in memory
without using sleep deprivation. One form of this approach has been used in human and animal studies performed by Elizabeth Hennevin and colleagues at the
University of Paris-South and Carlyle Smith at Trent
University in Canada (Hennevin et al. 1995; Smith 1995,
1996). These workers capitalized on the observation that
the learning curves of individual subjects do not show
improved performance in a smooth incremental fashion,
as the classical group learning curve is usually shown.
For individuals, small daily improvements occur, and
then, on a particular day, a large improvement in performance will occur. This pattern persists until performance reaches a plateau. Hennevin’s and Smith’s groups
observed a marked increase in the amount of REM sleep
during the sleep period just prior to a session in which
there was a large improvement in performance. The clear
inference is that during the increased amount of REM
sleep time, a greater amount of memory processing had
occurred – and the subsequent session showed the improved performance. When performance leveled off and,
presumably, no further memory consolidation had occurred, the amount of REM sleep returned to the baseline
levels that had been measured during sleep prior to the
learning sessions.
Recent work by Stickgold et al. (2000a, 2000b), using
human subjects, showed that improved performance did
not occur after learning trials unless sleep was permitted
within 30 h of the training. They further showed that
memory consolidation is a two-step process. The amount
of performance increase following a night’s sleep was
proportional to the amount of slow-wave sleep during the
first 2 h of sleep and also proportional to the amount of
REM sleep during the last 2 h of sleep. Their data support
the contention that slow-wave sleep during the beginning
hours of sleep and REM sleep toward the morning are
both important for the consolidation process.
A great deal of effort is currently directed toward exploring whether certain types of learning and memory are
selectively consolidated during REM sleep versus nonREM sleep (Smith 1996, 2001; Plihal and Born 1997,
1999; Gais et al. 2000; Stickgold et al. 2000a, 2000b;
Ribeiro et al. 2002; Davis et al. 2003; Graves et al. 2003).
Numerous theories have been proposed for the salutary
effect of sleep on memory consolidation. These range
from a form of practice or rehearsal during dream sleep
(Fishbein and Gutwein 1977, 1981) to neuromolecular
changes such as increased protein synthesis during sleep
that strengthen recent memory traces (Ramm and Smith
1990; Nakanishi et al. 1997; Van Cauter and Spiegel
1999; Frank et al. 2001; McDermott et al. 2003). The
role of sleep in memory is a heavily researched topic and
is by no means settled. Numerous review and research
papers have been written on this topic (Smith 1996, 2001;
Buzsaki 1998; Graves et al. 2001; Maquet 2001; Siegel
2001; Stickgold et al. 2001; Pace-Schott and Hobson
2002).
363
This broad-ranging review on sleep and waking has
presented historical material that has been basic to the
current advances in research on this topic. The nuclei and
neural circuits of the brain stem and other subcortical
areas that control waking, slow-wave sleep, and REM
sleep were described. Finally, functions of sleep related to
the immune system and memory were discussed.
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